WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 5 ;
C07C 233/29, 235/38, 275/34, C07D
213/36, 213/63, 213/75, A61K 31/165
Al
(11) International Publication Number: WO 94/22807
(43) International Publication Date: 13 October 1994 (13.10.94)
(21) International Application Number: PCT/EP94/01008
(22) International Filing Date: 30 March 1994 (30.03.94)
(30) Priority Data:
0411/93
7 April 1993 (07.04.93)
DK
(71) Applicant (for all designated States except US): NEU-
ROSEARCH A/S [DK/DK]; Smedeland 26B, DK-2600
Glostrup (DK).
(72) Inventors; and
(75) Inventors/Applicants (for US only): OLESEN, S0ren-Peter
[DK/DK]; Emiliekildevej 43, DK-2930 Klampenborg (DK).
MOLDT, Peter [DK/DK]; Langebjergvej 355, DK-3050
Humlebaek (DK). PEDERSEN, Ove [DK/DK]; Brpnd-
by0ster Torv 56, 3.tv., DK-2650 Hvidovre (DK).
(74) Agent: GRUNECKER, KINKELDEY, STOCKMAIR &
PARTNER; Maximilianstrasse 58, D-80538 Miinchen
(DE).
(81) Designated States: AU, BB, BG, BR, BY, CA, CN, CZ, FT,
HU, JP, KP, KR, KZ, LK, LV, MG, MN, MW, NO, NZ,
PL, RO, RU, SD, SK UA, US, UZ, VN, European patent
(AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC,
NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA,
GN, ML, MR, NE, SN, TD, TG).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments.
(54) Title: UREA AND AMIDE DERIVATIVES AND THEIR USE IN THE CONTROL OF CELL MEMBRANE POTASSIUM
CHANNELS
(57) Abstract
A compound having formula (I) or a pharmaceutically acceptable salt thereof, wherein X and Z each independently are NH or CH2,
at least one of X and Z being NH; Y is O, S, NCN, or NH; B, D, E and F each independently are C or N, at least three of B, D, E, and F
being C; and R 1 , R 2 , R 3 , R 4 , R 11 , R 12 have the meanings set forth in the specification, pharmaceutical compositions comprising the same,
and a method of treating therewith. The compounds are useful as potassium channel openers.
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
applications under the PCT.
AT
Austria
GB
United Kingdom
MR
Mauritania
AU
Australia
GE
Georgia
MW
Malawi
BB
Barbados
GN
Guinea
NE
Niger
BE
Belgium
GR
Greece
NL
Netherlands
BF
Burkina Faso
HU
Hungary
NO
Norway
BG
Bulgaria
IE
Ireland
NZ
New Zealand
Bj
Benin
rr
Italy
PL
Poland
BR
Brazil
jp
Japan
PT
Portugal
BY
Belarus
KE
Kenya
RO
Romania
CA
Canada
KG
Kyrgystan
RU
Russian Federation
CF
Central African Republic
KP
Democratic People's Republic
SD
Sudan
CG
Congo
of Korea
SE
Sweden
CH
Switzerland
KR
Republic of Korea
SI
Slovenia
CI
C6te d'lvoire
KZ
Kazakhstan
SK
Slovakia
CM
Cameroon
LI
Liechtenstein
SN
Senegal
CN
China
LK
Sri Lanka
TD
Chad
CS
Czechoslovakia
LU
Luxembourg
TG
Togo
CZ
Czech Republic
LV
Latvia
TJ
Tajikistan
DE
Germany
MC
Monaco
TT
Trinidad and Tobago
DK
Denmark
MD
Republic of Moldova
UA
Ukraine
ES
Spain
MG
Madagascar
US
United States of America
Fi
Finland
ML
Mali
UZ
Uzbekistan
FR
France
MN
Mongolia
VN
Viet Nam
GA Gabon
WO 94/22807
PCT/EP94/01008
1
UREA AND AMIDE DERIVATIVES AND THEIR USE IN THE CONTROL OF CELL MEMBRANE
POTASSIUM CHANNELS
The present invention relates to novel urea derivatives, a method of preparing
the same, a method of treatment with the novel urea derivatives, and to
pharmaceutical corn-positions comprising the same.
Object of the Invention
It is an object of the present invention to provide novel urea compounds which
are useful in the treatment of disorders or diseases of a living animal body,
including a human, and especially in the treatment of disorders or diseases
which can be treated by opening cell membrane potassium channels of such a
living animal body.
Another object of the present invention is to provide a method of treating
disorders or diseases of a living animal body, including a human, which
disorders or diseases are responsive to opening of potassium channels and
which comprises administering to such a living animal body in need thereof a
compound of the invention.
A third object of the present invention is to provide novel pharmaceutical
compositions for the treatment of disorders or diseases of a living animal body,
including a human, which disorders or diseases are responsive to the opening of
potassium channels.
Other objects will be apparent to the person skilled in the art hereinafter.
Background of the Invention
European patent application Publication No 477 819 discloses that certain
compounds are openers of BK channels.
WO 94/22807
PCT/EP94/01008
2
It is generally well known that opening of potassium (K+) channels leads to a
hyperpolarization and relaxation of cells. The presently known K+ channel
openers (e.g. cromakalim and pinacidil) exert their effect primarily by interaction
with the K+ channel subtype K A tp- These compounds have a high affinity for
vascular smooth muscle cells and are thus mostly vasodilators. Recent studies
indicate, however, that K+ channel openers hyperpolarizing neuronal cells also
have anticonvulsive and antiischemic effects in the central nervous system (the
CNS), European Journal of Pharmacology i§Z, 181-183 (1989), Neuroscience
Letters 11£, 195-200 (1990), Neuroscience 37M). 55-60 (1990), The Journal of
Pharmacology and Experimental Therapeutics 251m. 98-104 (1989).
Furthermore recent studies demonstrate that potassium channel openers acting
on airways smooth muscle (tracheal smooth muscle) cells will have anti-
asthmatic effects (Williams et a!., The Lancet 3_2£, 334-336 (1990)).
There exist other K+ channel sybtypes than K A tp, and one such subtype is the BK
channel, also called the maxi-K channel or large-conductance Ca2+ dependent
K+ channel. The BK channel is present in many cells including most central and
peripheral nerve cells, striated muscle cells, smooth muscle cells of the airways,
the vasculature, the gastrointestinal tract and bladder, in endo- and exocrine
glands including pancreatic B-cells and in kidney tubules (R. Latorre et al., Annu.
Rev. Physiol. 5J., 385 (1989)).
A scorpion toxin peptide, charybdotoxin, which blocks the BK channel fairly
specific has been used to demonstrate that the BK channel plays an important
role as a relaxing negative feed-back when the cells in these tissues become
highly active or spastic (J.E. Brayden and M.T. Nelson, Science 256_, 532 (1992);
T.R. Jones et al., J. Pharmacol. Exp. Ther. 255, 697 (1990); R. Robiteille and M.P.
Charlton, J. Neurosci. 12, 297 (1992); G. Suarez-Kurtz et al., J. Pharmacol. Exp.
Ther. 252, (1991)).
WO 94/22807
PCT/EP94/01008
3
Summary of the Invention
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula
or a pharmaceutical^ acceptable salt thereof,
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B.D.E and F each independently are C or N, at least three of B, D, E, and F being
C;
FP and R< each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN, alkoxy,
hydroxy, hydroxymethyl, sulphamoyl, aryloxy, alkylcarbonyl, arylcarbonyl,
arylcarbonyloxy, alkylcarbonyloxy;
R3 is hydrogen, halogen, COOH, COO-alkyl, COO-aryl, CO-amino, CN, alkoxy,
hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy, alkylcarbonyl,
arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
WO 94/22807
4
PCT/EF94/01008
R2 and R3 or R3 and R* together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of Rn and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxym ethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonylbxy and the
other of R11 and R12 is hydrogen, halogen, OCF 3) CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyclic ring which may be fully or partially
unsaturated, and
a compound as above which is
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
WO 94/22807
5
PCT7EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthy!) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1 -naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-(phenylamino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
or a pharmaceutically acceptable salt thereof, and
a pharmaceutical composition comprising a therapeutically effective amount of a
compound as any above together with at least one pharmaceutically acceptable
carrier, and
a method of treating a disorder or disease of a living animal body, including a
human, which disorder or disease is responsive to opening of potassium
channels and which comprises administering to such a living animal body,
including a human in need thereof an effective amount of a compound having
the formula
WO 94/22807 PCT/EP94/01008
6
or a pharmaceutical^ acceptable salt thereof,
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B,D,E and F each independently are C or N, at least three of B, D, E, and F being
C;
R1 and R* each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
R3 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of R11 and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy and the
other of R11 and R12 is hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
WO 94/22807
7
PCT/EP94/01008
A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyclic ring which may be fully or partially
unsaturated, and
the method as above wherein arterial hypertension, coronary artery spasms,
asthma, irritable bowl syndrome, spastic bladder, ischemia, psychosis, or
convulsions are treated, and
the method as any above wherein the compound is administered in the form of a
pharmaceutical composition thereof, in which it is present together with a
pharmaceutical^ acceptable carrier or diluent, and
the method as any above wherein
N-(1-naphthyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(2-hydroxy-5-chlorophenyl)-3-(trifiuoromethyl)phenylacetic amide,
N-(3, 5-dichlorophenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N , -(2-hydroxy-5-(trifluoromethyl)phenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N , -(2-hydroxy-5-chlorophenyl) thiourea,.
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-carboxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-methoxycarbonylphenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
WO 94/22807
8
PCT/EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-4-nitrophenyl) urea,
N-(3-(trifiuoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1 -naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N , -(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-tert-butylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethyi)phenyl)-N*-(2-hydroxy-4-aminophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-(phenylarnino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, is employed, and
the use of a compound having the formula
or a pharmaceutical^ acceptable salt thereof,
WO 94/22807
9
PCT/EP94/01008
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B,D,E and F each independently are C or N, at least three of B, D, E, and F being
C;
Ri and R4 each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, halogen, CF 3l COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
R3 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of Rn and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy and the
other of R11 and R12 is hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
WO 94/22807
10
PCT/EP94/01008
A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyclic ring which may be fully or partially
unsaturated, for the manufacture of a medicament for the treatment of a disorder
or disease of a living animal body, including a human, which disorder or disease
is responsive to opening of potassium channels, and
the use of a compound having the formula
or a pharmaceutical^ acceptable salt thereof,
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B.D.E and F each independently are C or N, at least three of B, D, E, and F being
C;
Ri and R4 each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxym ethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
WO 94/22807
11
PCT/EP94/01008
R3 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkyicarbonyl, arylcarbonyl, aryicarbonyloxy, alkylcarbonyloxy; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of R11 and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkyicarbonyl, arylcarbonyl, aryicarbonyloxy, alkylcarbonyloxy and the
other of R11 and R12 is hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkyicarbonyl, arylcarbonyl, aryicarbonyloxy, alkylcarbonyloxy;
A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyclic ring which may be fully or partially
unsaturated, for the manufacture of a medicament for the treatment of arterial
hypertension, coronary artery spasms, asthma, irritable bowl syndrome, spastic
bladder, ischemia, psychosis, or convulsions, and
the use as above wherein the compound employed is
N-(1 -naphthyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide,
N-(3, 5-dichlorophenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N , -(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-carboxyphenyl) urea,
WO 94/22807
PCT/EP94/01008
12
N-(3-(trifluoromethyl)phenyi)-N'-(2-hydroxy-4-nitro-5-methoxycarbonylphenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifiuoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifiuoromethyl)phenyl)-N'-(2-hydroxy-5-methoxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1-naphthyi) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-tert-butylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-aminophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-(phenylamino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, and
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13
a method of preparing a compound as first above, comprising the step of
a) reacting a compound having the formula
R 11 H
H — — NCG
R 1 *A
wherein A, R11 and R12 have the meanings set forth in claim 1 , and G is O or S
with a compound having the formula
QO R 1
H 2 N-<\ „D-R 2
R 4 R 3
wherein B, D, E, F, R1, R2, R3 and R4 have the meanings set forth in claim 1 and Q
is H or CH 3 as necessary, followed by deprotection with BBr 3 in case Q is CH 3 , or
b) reacting a compound having the formula
wherein A, R11 and R12 have the meanings set forth in claim 1, with a compound
having the formula
H 3 CO x R 1
GCN— ( x ,D-R 2
R 4 R 3
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wherein B, D, E, F, FP, R2, R3 and R4 have the meanings set forth in claim 1, and
G is O or S followed by deprotection with BBr 3 , or
c) reacting a compound having the formula
R 11 H
•C0 2 H
wherein A, Rn and R12 have the meanings set forth in claim 1 with a compound
having the formula
H 3 CO, R 1
H 2 N— (\ „D-R 2
F-E
R 4 R 3
wherein B, D, E, F, Ri, R2, R3 an d R* have the meanings set forth in claim 1, using
dicyclohexyicarbodiimide as coupling agent followed by deprotection with BBr 3 ,
or
d) reacting a compound having the formula
R 11 H
H— / V-NH 2
R 12 A
wherein A, R11 and R12 have the meanings set forth in claim 1 with a compound
having the formula
H3CO R 1
H0 2 C-< N t D— R 2
R 4 R 3
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PCT/EP94/01008
wherein B, D, E, F, FP, R2, R3 and R* have the meanings set forth in claim 1 using
dicyclohexylcarbodiimide as coupling agent followed by deprotection with BBr 3l
or
e) reacting a compound having the formula
R 11 H
H— f \-NHCN
wherein A, Rn and R12 have the meanings set forth in claim 1 with a compound
having the formula
H 3 CO v R 1
-CI + H 3 N— ( N # D-R 2
R 4 R 3
wherein B, D, E, F, R1, R2, R3 an d R4 have the meanings set forth in claim 1
followed by deprotection with BBr 3 , or
f) reacting a compound having the formula
R 11 H
H— / \-NH 3 + cr
R 12 A
wherein A, R11 and R12 have the meanings set forth in claim 1 with a compound
having the formula
H 3 CO v R 1
NCHN— ( x ,D-R 2
R R 3
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PCT/EP94/01008
wherein B, D, E, F, Ri, R2, R3 and R4 have the meanings set forth in claim 1
followed by deprotection with BBr3, or
g) reacting a compound having the formula
wherein X, Z, A, B, D, E, F, Ri, R2, R3, R4. rh and R12 have the meanings set forth
in claim 1 with Lawesson's Reagent or P 2 S 5 followed by deprotection with BBr 3i
and
a method as above wherein
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
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PCT/EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1-naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-ben2oylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, is prepared.
Halogen is fluorine, chlorine, bromine, or iodine.
Alkyl means a straight chained or branched chain of from one to six carbon
atoms, cyclic alkyl of from three to seven carbon atoms, or cycloalkylalkyl,
including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl;
methyl, ethyl, propyl and isopropyl are preferred groups.
Alkoxy means O-alkyl, wherein alkyl is as defined above.
Acyl means (C=0)-alkyl wherein alkyl is as defined above.
Amino means NH 2 or NH-alkyl, N-(alkyl) 2 , NH-acyl, NH-phenyl or N(acyl) 2 .
Sulphamoyl means S0 2 -amino, wherein amino is as defined above.
Examples of pharmaceutically-acceptable addition salts include inorganic and
organic acid addition salts such as the hydrochloride, hydrobromide, phosphate,
nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate,
mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate,
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methanesulfonate, stearate, succinate, glutamate, glycollate, toluene-p-
sulphonate, formate, malonate, naphthalene-2-sulphonate, salicylate and the
acetate. Such salts are formed by procedures well known in the art.
Other acids such as oxalic acid, while not in themselves pharmaceutically
acceptable may be useful in the preparation of salts useful as intermediates in
obtaining compounds of the invention and their pharmaceutically acceptable
acid addition salts.
Further, the compounds of this invention may exist in unsolvated as well as in
solvated forms with pharmaceutically acceptable solvents such as water, ethanol
and the like. In general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention exist in (+) and (-) forms as well
as in racemic forms. Racemic forms can be resolved into the optical antipodes by
known methods, for example, by separation of diastereomeric salts thereof, with
an optically active acid, and liberating the optically active amine compound by
treatment with a base. Another method for resolving racemates into the optical
antipodes is based upon chromatography on an optical active matrix. Racemic
compounds of the present invention can thus be resolved into their optical
antipodes, e.g., by fractional crystallization of d- or I- (tartrates, mandelates, or
camphorsulphonate) salts for example.
The compounds of the present invention may also be resolved by the formation
of diastereomeric amides by reaction of the compounds of the present invention
with an optically active activated carboxylic acid such as that derived from (+) or
(-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the
formation of diastereomeric carbamates by reaction of the compounds of the
present invention with an optically active chloroformate or the like.
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Additional methods for the resolvation of optical isomers, known to those skilled
in the art may be used, and will be apparent to the average skilled in the art.
Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in
"Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York
(1981).
Starting materials for the processes described in the present application are
known or can be prepared by known processes from commercially available
chemicals.
The products of the reactions described herein are isolated by conventional
means such as extraction, crystallization, distillation, chromatography, and the
like.
Biology
The compounds of the present invention are potent openers of the high
conductance BK channel, and the ability of the compounds of the present
invention to open the BK channel can be demonstrated in several ways.
All experiments were performed with patch-clamp technique (Hamill et al.,
Pflugers Arch. 391, 85-100 (1981)). The ion composition of the internal solution
was (in mM) 140 KCI, 1 CaCI 2 , 1 MgCI 2 , 2 EGTA, 10 HEPES and the external
solution contained 140 NaCI, 4 KCI, 2 CaCI 2 , 1 MgCI 2 and 10 HEPES.
Whole Cell Rpnnrding g
The membrane currents of calf aortic smooth muscle cells were determined in
whole-cell recordings using voltage clamp mode (HEKA EPC-9 patch-clamp
amplifier). Administration of N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-
chlorophenyl) urea to the bath at concentrations of 1-10 u.M specifically activated
BK currents, which were blockable by charybdotoxin, by increasing the outward
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20
current by up to 10 times and shifting the activation curve by more than -60 mV
towards negative membrane potentials.
A selective activation of BK currents was also found in cultured cortical neurons,
cerebellar granule cells, PC12 cells and in human coronary atery smooth muscle
cells. No effect was found on Na+ currents or voltage-dependent K+ currents (A
type, delayed rectifier type) also present in the neuronal cells.
Single Channel Experiments
In inside-out patches of human coronary atery smooth muscle cell membrane
single BK channels were activated by for example N-(3-(trifluoromethyl)phenyl)-
N'-(2-hydroxy-5-chlorophenyl) urea (1-10u.M). This compound increased the
open probability of the BK channel with several hundred percent.
Likewise in cultured bovine aortic smooth muscle cells in which the BK channel
is the predominant K+ channel for example N-(3-(trifluoromethyl)phenyl)-N'-(2-
hydroxy-5-chlorophenyl) urea (1 u.M) significantly activated the BK channel. The
BK channels were also activated by N-(3-(trifluoromethyl)phenyl)-N*-(2-hydroxy-
5-chlorophenyl) urea and N-phenyl-N'-(2-hydroxy-5-chlorophenyl) urea at
concentrations equal or greater than 3u.M and by N-(3-(trifluoromethyl)phenyl)-
N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea at concentrations greater than
10u.M.
Guinea-Pig Ileum Experiment
The compound, N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-
chlorophenyl) urea, has been studied for its ability to relax acetylcholine-
contracted guinea-pig ileum. The smooth muscle cells of the ileum express many
BK channels and the model predicts relaxing effects on the gastrointestinal or
urogenital tracts. The above mentioned compound relaxes the ileum in a dose-
dependent way (3-30 uM).
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Method: Ileum from guinea-pigs are isolated and mounted in an isometric
contraction chamber. It is bathed in a physiological Krebs solution at 98°F. The
ileum is precontracted with increasing concentrations of acetylcholine (0.015-5.0
u.M). The contractions are reversed by including the compound in the bathing
solution.
Cocaine Experiment
The compound, N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl)
urea, has been studied in the cocaine motility test. Cocaine induces hypermotility
due to an inhibition of dopamine reuptake. The test is recognized as a test
predicting anti-psychotic activity. The above mentioned compound (10-30 mg/kg)
antagonizes cocaine induced hypermotility according to the test procedure
described below.
Meihod: Two female NMRI mice (20-25 g) are placed in each test box (normal
transparent plexiglas cage, w, I, h = 21 x 39 x 19 cm) in the test room for at least
16 hours with food and water ad libitum before the test in order for the animals to
habituate to the situation.The test compound is administered i.p. 15 min before
saline or 25 mg/kg cocaine i.p. to 32 mice (16 boxes) per dose. Food and water
are withdrawn, and the motility is measured as the number of interrupted infra-
red photo-beams (8 per box placed 5 cm apart and 3 cm over the bottom of the
cage) for the next 120 min.
These results also demonstrate that the compounds of the invention are potential
anti-psychotics acting by a novel discovered mechanism.
Pharmaceutical Compositions
While it is possible that, for use in therapy, a compound of the invention may be
administered as the raw chemical, then it is preferable to present the active
ingredient as a pharmaceutical formulation.
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PCT/EP94/01008
The invention thus further provides a pharmaceutical formulation comprising a
compound of the invention or a pharmaceutically acceptable salt or derivative
thereof together with one or more pharmaceutically acceptable carriers therefore
and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s)
must be "acceptable" in the sense of being compatible with the other ingredients
of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical
(including buccal and sub-lingual), vaginal or parenteral (including
intramuscular, sub-cutaneous and intravenous) administration or in a form
suitable for administration by inhalation or insufflation.
The compounds of the invention, together with a conventional adjuvant, carrier,
or diluent, may thus be placed into the form of pharmaceutical compositions and
unit dosages thereof, and in such form may be employed as solids, such as
tablets or filled capsules, or liquids such as solutions, suspensions, emulsions,
elixirs, or capsules filled with the same, all for oral use, in the form of
suppositories for rectal administration; or in the form of sterile injectable solutions
for parenteral (including subcutaneous) use. Such pharmaceutical compositions
and unit dosage forms thereof may comprise conventional ingredients in
conventional proportions, with or without additional active compounds or
principles, and such unit dosage forms may contain any suitable effective
amount of the active ingredient commensurate with the intended daily dosage
range to be employed. Formulations containing ten (10) milligrams of active
ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are
accordingly suitable representative unit dosage forms.
The compounds of the present invention can be administrated in a wide variety
of oral and parenteral dosage forms. It will be obvious to those skilled in the art
that the following dosage forms may comprise as the active component, either a
compound of the invention or a pharmaceutically acceptable salt of a compound
of the invention.
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PCT/EFM/01008
For preparing pharmaceutical compositions from the compounds of the present
invention, pharmaceutical^ acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules, cachets,
suppositories, and dispersible granules. A solid carrier can be one or more
substances which may also act as diluents, flavouring agents, solubilizers,
lubricants, suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely
divided active component.
In tablets, the active component is mixed with the carrier having the necessary
binding capacity in suitable proportions and compacted in the shape and size
desired.
The powders and tablets preferably contain from five or ten to about seventy
percent of the active compound. Suitable carriers are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting vax,
cocoa butter, and the like. The term "preparation" is intended to include the
formulation of the active compound with encapsulating material as carrier
providing a capsule in which the active component, with or without carriers, is
surrounded by a carrier, which is thus in association with it. Similarly, cachets
and lozenges are included. Tablets, powders, capsules, pills, cachets, and
lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting vax, such as a mixture of fatty acid
glycerides or cocoa butter, is first melted and the active component is dispersed
homogeneously therein, as by stirring. The molten homogenous mixture is then
poured into convenient sized molds, allowed to cool, and thereby to solidify.
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PCT/EP94/01008
Formulations suitable for vaginal administration may be presented as pessaries,
tampons, creams, gels, pastes, foams or sprays containing, in addition to the
active ingredient, such carriers as are known in the art to be appropriate.
Liquid form preparations include solutions, suspensions, and emulsions, for
example, water or water propylene glycol solutions. For example, parenteral
injection liquid preparations can be formulated in solutions in aqueous
polyethylene glycol solution.
The compounds according to the present invention may thus be formulated for
parenteral administration (e.g. by injection, for example bolus injection or
continuous infusion) and may be presented in unit dose form in ampoules, pre-
filled syringes, small volume infusion or in multi-dose containers with an added
preservative. The compositions may take such forms as suspensions, solutions,
or emulsions in oily or aqueous vehicles, and may contain formulatory agents
such as suspending, stabilising and/or dispersing agents. Alternatively, the
active ingredient may be in powder form, obtained by aseptic isolation of sterile
solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g.
sterile, pyrogen-free water, before use.
Aqueous solutions suitable for oral use can be prepared by dissolving the active
component in water and adding suitable colorants, flavours, stabilizing and
thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely
divided active component in water with viscous material, such as natural or
synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and
other well known suspending agents.
Also included are solid form preparations which are intended to be converted,
shortly before use, to liquid form preparations for oral administration. Such liquid
forms include solutions, suspensions, and emulsions. These preparations may
contain, in addition to the active component, colorants, flavours, stabilizers,
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buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing
agents, and the like.
For topical administration to the epidermis the compounds according to the
invention may be formulated as ointments, creams or lotions, or as a transdermal
patch. Ointments and creams may, for example, be formulated with an aqueous
or oily base with the addition of suitable thickening and/or gelling agents. Lotions
may be formulated with an aqueous or oily base and, in general, will also
contain one or more emulsifying agents, stabilizing agents, dispersing agents,
suspending agents, thickening agents, or colouring agents.
Formulations suitable for topical administration in the mouth include lozenges
comprising active agent in a flavoured base, usually sucrose and acacia or
tragacanth; pastilles comprising the active ingredient in an inert base such as
gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasel cavity by conventional
means, for example with a dropper, pipette or spray. The formulations may be
provided in single or multidose form. In the latter case of a dropper or pipette this
may be achieved by the patient administering an appropriate, predetermined
volume of the solution of suspension. In the case of a spray this may be achieved
for example by means of a metering atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of an
aerosol formulation in which the active ingredient is provided in a pressurized
pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example
dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane,
carbon dioxide or other suitable gas. The aerosol may conveniently also contain
a surfactant such as lecithin. The dose of drug may be controlled by provision of
a metered valve.
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PCT/EP94/01008
Alternatively the active ingredients may be provided in the form of a dry powder,
for example a powder mix of the compound in a suitable powder base such as
lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and
polyvinylpyrrolidine (PVP). Conveniently the powder carrier will form a gel in the
nasal cavity. The powder composition may be presented in unit dose form for
example in capsules or cartridges of e.g. gelatin or blister packs from which the
powder may be administered by means of an inhaler.
In formulations intended for administration to the respiratory tract, including
intranasal formulations, the compound will generally have a small particle size
for example of the order of 5 microns or less. Such a particle size may be
obtained by means known in the art, for example by micronization.
When desired, formulations adapted to give sustained release of the active
ingredient may be employed.
The pharmaceutical preparations are preferably in unit dosage forms. In such
form, the preparation is subdivided into unit doses containing appropriate
quantities of the active component. The unit dosage form can be a packaged
preparation, the package containing discrete quantities of preparation, such as
packeted tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the
appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous
administration are preferred compositions.
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Method of Treating
The compounds of this invention are extremely useful in the treatment of
disorders or diseases of mammals due to their potent potassium channel
activating properties. These properties make the compounds of this invention
extremely useful in the treatment of potassium channel dependent convulsions,
potassium channel dependent asthma, potassium channel dependent arterial
hypertension, potassium channel dependent coronary artery spasms, potassium
channel dependent irritable bowl, potassium channel dependent spastic
bladder, potassium channel dependent ischemia, and other disorders sensitive
to potassium channel activating activity. The compounds of this invention may
accordingly be administered to a subject, including a human, in need of
treatment, alleviation, or elimination of an indication associated with the
potassium channels. This includes especially convulsions and every form of
epilepsia, asthma, hypertension, spastic bladder, irritable bowl, coronary artery
spasms, aterial hypertension, psychosis and ischemia.
Suitable dosage range are 0.1-1000 milligrams daily, 10-500 milligrams daily,
and especially 30-100 milligrams daily, dependent as usual upon the exact
mode of administration, form in which administered, the indication toward which
the administration is directed, the subject involved and the body weight of the
subject involved, and further the preference and experience of the physician or
veterinarian in charge.
The following examples will illustrate the invention further, however, they are not
to be construed as limiting.
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EXAMPLE 1
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea
2-hydroxy-5-nitroaniline (1.25 g, 8.1 mmol) and 3-(trifluoromethyl)phenyl
isocyanate (1.00 ml, 7.3 mmol) were added to toluene (50 ml). The reaction
mixture was stirred at RT overnight, the product filtered off and recrystallized
from methanol/water 8:1 (45 ml).
1.39 g (56%) of the title compound was isolated. M.p. 226°C (dec).
The following compounds were prepared in a similar manner.
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dimethoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-(phenylamino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea. M.p. 199-200°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea. M.p. 171-
173°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-tert-butylphenyl) urea. M.p. 173-
174°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea. M.p. 153-
154°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-(trifluoromethyl)phenyl) urea. M.p.
192-194°C,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea. M.p. 184-188°C
(dec),
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxyl-2-pyridyl) urea. M.p. 181-183°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1-naphthyl) urea. M.p. 187-189°C
(dec),
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-chlorophenyl) urea. M.p. 169-
171°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea. M.p. 174-175°C,
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N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea. M.p. 178-179°C,
N-(3-(trifluoror;v3thyl)phenyl)-N'-(2, 5-dimethoxy-4-nitrophenyl) urea,
N-(3-(trifiuoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea. M.p.
222-223°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea. M.p. 223-224°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 6-dimethoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea. M.p.
>310°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea. M.p. 173-
174°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-methoxycarbonyl-4-nitrophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-4-nitrophenyi) urea. M.p.
201-203°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea. M.p. 173-174°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-4-nitro-5-carboxyphenyl) urea.
EXAMPLE 2
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-aminophenyl) urea.
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea (1.00 g, 2.9
mmol) was subjected to catalytic reduction in tetrahydrofuran (50 ml) using 5%
palladium on carbon (0.20 g). The reaction mixture was filtered through a path of
celite. Evaporation of the filtrate and subsequent recrystallization of the crude
product from methanol/water 1:1 (50 ml) afforded the title compound. 0.68 g
(75%) of the title compound was isolated. M.p. 200-202°C.
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EXAMPLE 3
N-(1 -naphthyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea.
2-hydroxy-5-(trifluoromethyl)aniline (0.12 g, 0.7 mmol) in toluene (3 ml) was
added to a solution of alpha-naphthyl isocyanate (0.11 g, 0.7 mmol) in toluene (3
ml). The reaction was stirred at RT overnight and the product filtered off. 0.17 g
(72%) of the title compound was isolated. M.p. 205-207°C.
EXAMPLE 4
N-(2-methoxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide.
Dicyclohexylcarbodiimide (2.20 g, 10.7 mmol) was added to a solution of 3-
(trifluoromethyl)phenylacetic acid (2.00 g, 9.8 mmol) and 5-chloro-2-
methoxyaniline (1.55 g, 9.8 mmol) in dichloromethane (50 ml). The reaction wa
stirred at RT overnight. The reaction mixture was filtered and the filtrate
evaporated to dryness. The residue was recrystallized from methanol/water 2:1
(30 ml). 2.05 g (61%) of the title compound was isolated.
The following compound was prepared in a similar manner.
N-(3-(trifluoromethyl)phenyl)-2-methoxy-5-chlorophenylacetic amide starting
from 3-trifluoromethylphenylamine and 2-methoxy-5-chlorophenylacetic acid.
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EXAMPLE 5
N^S.S-dichlorophenylJ-N'-ta-methoxy-S-CtrifluoromethyOphenyl) urea
3,5-dichlorophenyl isocyanate (0.94 g, 5.0 mmol) in toluene (10 ml) was added
to a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.96 g, 5.0 mmol) in toluene
(10 ml). The reaction was stirred at RT for 1 hour and the product filtered off. 1.20
(63%) of the title compound was isolated.
EXAMPLE 6
N-(5,6,7,8-tetrahydro-1-naphthyl)-N'-(2-methoxy-5-(trifluoromethyl)phenyl) urea.
2- methoxy-5-(trifluoromethyl)phenyl carbamoylchloride (0.81 g, 3.2 mmol), 1-
amino-5,6,7,8-tetrahydronaphtalene (445 ul, 3.2 mmol) and triethylamine (446 u.l,
3.2 mmol) were added to chloroform (20 ml) and the resulting mixture was stirred
at RT overnight. The reaction mixture was poured into water and extracted with
ethyl acetate. The solvent was evaporated in vacuuo and the residue
recrystallized from toluene (20 ml). 0.45 g of the title compound was isolated.
EXAMPLE 7
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-(trifluoromethyl)phenyl) thiourea.
3- (trifluoromethyl)phenyl isothiocyanate in toluene (0.76 ml, 5.0 mmol) was
added to a solution of 2-methoxy-5-(trifiuoromethyl)aniline in toluene (10 ml).
The resulting reaction mixture was stirred at RT overnight and the product was
subsequently filtered off. 1.00 g (51%) of the title compound was isolated.
The following compound was prepared in a similar manner.
N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-chlorophenyl) thiourea.
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EXAMPLE 8
N-(3-methoxycarbonylphenyl)-N'-(2-methoxy-5-chlorophenyl) urea.
N-(3-carboxyphenyl)-N'-(2-methoxy-5-chlorophenyl) urea (3.00 g, 9.4 mmol) was
suspended in methanol (100 ml). Concentrated sulfuric acid (1.0 ml) was added
and the reaction was heated at reflux for 6 hours. The reaction mixture was
poured into cold (0°C) water (600 ml). Filtration of the suspension afforded the
crude product. The crude product was purified by column chromatography on
silica using dichloromethane/eihyl acetate 19:1 as eluent. 2.35 g of the title
compound was isolated.
EXAMPLE 9
• 1 -(3-(trifluoromethyl)phenyl-3-(2-methoxy-5-chlorophenyl) guanidine.
A mixture of 3-(trifluoromethyl)phenylcyanamide (2.00 g, 10.7 mmol) and 5-
chloro-2-methoxyaniline hydrochloride (2.30 g, 11.8 mmol) was suspended in
acetonitrile (80 ml). The reaction was heated at reflux for four days. The solvent
was evaporated in vacuo. The residue was redissolved in dichloromethane (100
ml) and washed with a saturated sodium bicarbonate solution. The crude product
was purified by column chromatography on silica gel initially using
dichloromethane as eluent followed by dichloromethane/methanol 9:1 as eluent.
2.27 g of the title compound was obtained as a dark oil which slowly crystallises.
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EXAMPLE 10
N-(3-benzoylphenyl)-N'-(2-methoxy-5-chlorophenyl) urea.
A mixture of 5-chloro-2-methoxyphenyl isocyanate (1.00 g, 5.4 mmol) and 3-
aminobenzophenone (1.29 g, 6.5 mmol) was stirred in toluene (20 ml) for two
days. The reaction was filtered and the filter cake washed with toluene. 1 .9 g of
the title compound was isolated.
The following compounds were prepared in a similar manner.
N-(3-carbamoylphenyl)-N'-(2-methoxy-5-chlorophenyl) urea,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-methoxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-methoxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-methoxy-5-chlorophenyl) urea,
N-(3-nitrophenyl)-N'-(2-methoxy-5-chlorophenyl) urea, and
N-(3-carboxyphenyl)-N'-(2-methoxy-5-chlorophenyl) urea.
EXAMPLE 1 1
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(phenylamino)phenyl) urea
To a cold (0°C) suspension of N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-
(phenylamino)phenyl) urea (1.00 g, 2.5 mmol) in dichloromethane (50 ml), boron
tribromide (0.48 ml, 5.1 mmol) was added. After the addition of boron tribromide
the ice bath was removed and the reaction mixture was stirred for 3 hours at RT.
The reaction was poured on ice (10 ml) and 1 M sodium bicarbonate (50 ml) was
added. The aqueous phase was extracted with ethyl acetate (50 ml) and the
organic phase dried over magnesium sulfate. 1.05 g crude product was
obtained. The crude product was purified by column chromatography on silica
gel using petroleum ether/ethyl acetate 1:1 as eluent. The partly purified product
(0.61 g) was recrystallized from ethanol/water 1:1 (20 ml). 0.20 g (21%) of the title
compound was isolated. M.p. 166-168°C.
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The"following compounds were prepared in a similar manner.
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea, M.p. 165-168°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea, M.p.
160-162°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorobenzyl) urea, M.p. 56-66°C,
N-(3-(trifluoromethyl)phenyi)-N'-(2,3-dihydroxybenzyl) urea, M.p. 159-1 61 °C,
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide, M.p. 148-
153°C,
N-(3, 5-dichlorophenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea, M.p.
202°C,
N-(5,6,7,8-tetrahydro-1-naphthyl)-N'-(2-hydroxy-5-(trifiuoromethyl)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) thiourea,
M.p. 124-125°C,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, M.p. 179-180°C,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-nitrophenyi)-N'-(2-hydroxy-5-chlorophenyI) urea, M.p. 194-196°C,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, M.p. 216°C,
N-(3-ben2oylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, M.p. 205-206°C,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chIorophenyl) urea, M.p. 203-204°C,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, M.p. 158-
159°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxy-4-nitrophenyi) urea, M.p.
220-222°C,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, M.p. 182°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea, M.p. 179-180°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea, M.p. 176-
177°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3rpyridyl) urea, M.p. 223-
224°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-methoxycarbonylphenyl)
urea, M.p. 201 -202°C,
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N-(3-(trifluorcmethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea, M.p.
205-206°C,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea.
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-carboxyphenyl) urea, M.p.
201-203°C,
1-(3-(trifluoromethyl)phenyl-3-(2-hydroxy-5-chlorophenyl) guanidine, M.p. 172-
174°C, and
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide, M.p. 148-
150°C.
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Claims:
1. A compound having the formula
or a pharmaceutical^ acceptable salt thereof,
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B.D.E and F each independently are C or N, at least three of B, D, E, and F being
C;
Ri and R* each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN, alkoxy,
hydroxy, hydroxymethyl, sulphamoyl, aryloxy, alkylcarbonyl, arylcarbonyl,
arylcarbonyloxy, alkylcarbonyloxy;
R3 is hydrogen, halogen, COOH, COO-alkyl, COO-aryl, CO-amino, CN, alkoxy,
hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy, alkylcarbonyl,
arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
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R2 and R3 or R3 and R* together with the carbon atoms to which they are attached
form an additional fused carbocyciic ring which may be fully or partially
unsaturated;
at least one of Rn and R12 is halogen, OCF 3 , CF 3> COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy and the
other of R11 and R12 is hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
A is hydrogen or together with Ri2and the carbon atoms to which they are
attached form an additional fused carbocyciic ring which may be fully or partially
unsaturated.
2. A compound of claim 1 which is
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
N-'(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
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PCT/EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
N-(3-(trifluoromethy!)phenyl)-NX3-hydroxy-2-pyridyO urea,
N-(3-(trifluoromethyl)phenyI)-N'-(2-hydroxy-1 -naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trmuoromethyi)phenyl)-N'-(2-hydroxy-4-(phenylamino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
or a pharmaceutical^ acceptable salt thereof.
3 - A pharmaceutical composition comprising a therapeutically effective
amount of a compound of claim 1 together with at least one pharmaceutical^
acceptable carrier.
4. A method of treating a disorder or disease of a living animal body,
including a human, which disorder or disease is responsive to opening of
potassium channels and which comprises administering to such a living animal
body, including a human in need thereof an effective amount of a compound
having the formula
or a pharmaceutical^ acceptable salt thereof,
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PCT/EP94/01008
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B,D,E and F each independently are C or N, at least three of B, D, E, and F being
C;
Ri and each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
R3 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of R11 and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy and the
other of R" and R12 is hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
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A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyclic ring which may be fully or partially
unsaturated.
5. The method of claim 4 wherein arterial hypertension, coronary artery
spasms, asthma, irritable bowl syndrome, spastic bladder, ischemia, psychosis,
or convulsions are treated.
6. The method of claim 4 wherein the compound is administered in the
form of a pharmaceutical composition thereof, in which it is present together with
a pharmaceutical^ acceptable carrier or diluent.
7. The method of claim 4 wherein
N-(1-naphthyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide,
N-(3, 5-dichlorophenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-{2-hydroxy-5-(trifluoromethyl)phenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-carboxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-methoxycarbonylphenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
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PCT/EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyi) urea,
N-(3-(trifiuoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N"-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifiuoromethyl)phenyl)-N'-(2-hydroxy-1 -naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-tert-butylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N , -(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-aminophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-(phenylamino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, is employed.
8. The use of a compound having the formula
or a pharmaceutical^ acceptable salt thereof,
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wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B,D,E and F each independently are C or N, at least three of B, D, E, and F being
C;
Ri and R* each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
R3 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
R2 and R3 or R3 and R* together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of Rn and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy and the
other of R11 and R12 is hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
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A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyciic ring which may be fully or partially
unsaturated, for the manufacture of a medicament for the treatment of a disorder
or disease of a living animal body, including a human, which disorder or disease
is responsive to opening of potassium channels.
9. The use of a compound having the formula
or a pharmaceutical^ acceptable salt thereof,
wherein
X and Z each independently are NH or CH2, at least one of X and Z being NH;
Y is O, S, NCN, or NH;
B,D,E and F each independently are C or N, at least three of B, D, E, and F being
C;
Ri and FK each independently are hydrogen, halogen, CF 3 , COOH, COO-alkyl,
COO-aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl,
sulphamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy,
alkylcarbonyloxy;
R2 is hydrogen, halogen, CF 3 . COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
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PCT/EP94/01008
R3 is hydrogen, halogen, CF 3 , COOH, COO-alkyl, COO-aryl, CO-amino, CN,
alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino, aryloxy,
alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy; or
R2 and R3 or R3 and R* together with the carbon atoms to which they are attached
form an additional fused carbocyclic ring which may be fully or partially
unsaturated;
at least one of Rn and R12 is halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-aryl,
CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl, amino,
aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy and the
other of Rn and R12 j s hydrogen, halogen, OCF 3 , CF 3 , COOH, COO-alkyl, COO-
aryl, CO-amino, CN, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulphamoyl,
amino, aryloxy, alkylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkylcarbonyloxy;
A is hydrogen or together with R12 and the carbon atoms to which they are
attached form an additional fused carbocyclic ring which may be fully or partially
unsaturated, for the manufacture of a medicament for the treatment of arterial
hypertension, coronary artery spasms, asthma, irritable bowl syndrome, spastic
bladder, ischemia, psychosis, or convulsions.
10. The use according to claim 8 wherein the compound employed is
N-(1 -naphthyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(2-hydroxy-5-chlorophenyI)-3-(trifluoromethyl)phenylacetic amide,
N-(3, 5-dichlorophenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
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PCT/EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-carboxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitro-5-methoxycarbonylphenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N , -(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1 -naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-tert-butylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N*-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-(trifluoromethyl)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-aminopheriyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-(phenylamino)phenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea.
WO 94/22807 PCT/EP94/01008
46
11. A method of preparing a compound of claim 1 , comprising the step of
a) reacting a compound having the formula
R 11 H
H— ? \-NCG
R 12 A
wherein A, Rn and R12 have the meanings set forth in claim 1, and G is O or S
with a compound having the formula
QO R 1
H 2 N — (\ ,P-R 2
R 4 R 3
wherein B, D, E, F, Ri, R2, R3- a nd R4 have the meanings set forth in claim 1 and Q
is H or CH 3 as necessary, followed by deprotection with BBr 3 in case Q is CH 3 , or
b) reacting a compound having the formula
R 11 H
wherein A, R11 and R12 have the meanings set forth in claim 1, with a compound
having the formula
H3CO R 1
>=b;
GCN— (\ ,D-R 2
R 4 R 3 .
WO 94/22807
47
PCT/EP94/01008
wherein B, D, E, F, R1, R2, R3 and R4 have the meanings set forth in claim 1, and
G is O or S followed by deprotection with BBrs, or
c) reacting a compound having the formula
R 11 H
R 12 A
wherein A, Rn and R12 have the meanings set forth in claim 1 with a compound
having the formula
H3CO R 1
H 2 N— { ,D-R 2
R 4 R 3
wherein B, D, E, F, Ri, R2, R3 and R* have the meanings set forth in claim 1, using
dicyclohexylcarbodiimide as coupling agent followed by deprotection with BBr 3 ,
or
d) reacting a compound having the formula
R 11 H
R
12
wherein A, R11 and R12 have the meanings set forth in claim 1 with a compound
having the formula
H 3 C(3 R 1
H0 2 C-<\ D-R 2
R 4 R 3
wherein B, D, E, F, Ri, R2, R3 and R4 have the meanings set forth in claim 1 using
WO 94/22807 PCT/EP94/01008
48
dicyclohexylcarbodiimide as coupling agent followed by deprotection with BBr 3 ,
or
e) reacting a compound having the formula
R 11 H
H ~ \ / NHCN
R 12 A
wherein A, R11 and R12 have the meanings set forth in claim 1 with a compound
having the formula
H3CO R 1
•CI + H 3 N— (\ ,D-R 2
R 4 R 3
wherein B, D, E, F, Ri, R2, R3 and R< have the meanings set forth in claim 1
followed by deprotection with BBr3, or
f) reacting a compound having the formula
R 11 H
wherein A, R11 and R12 have the meanings set forth in claim 1 with a compound
having the formula
H3CO R 1
NCHN— (\ ,D-R 2
r-i
R 4 R 3
wherein B, D, E, F, R1, R2, R3 and R« have the meanings set forth in claim 1
followed by deprotection with BBr 3 , or
WO 94/22807
49
PCT/EP94/01008
g) reacting a compound having the formula
wherein X, Z, A, B, D, E, F, R1, R2, R3. R4. rh and R12 have the meanings set forth
in claim 1 with Lawesson's Reagent or P2S5 followed by deprotection with BBr 3 .
12. A method according to claim 1 1 wherein
N-(2-hydroxy-5-chlorophenyl)-3-(trifluoromethyl)phenylacetic amide,
N-(3-(trifluoromethoxy)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-2-hydroxy-5-chlorophenylacetic amide,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) thiourea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxycarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxycarbonyl-5-chlorophenyl)
urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxcarbonylphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-6-methoxy-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chloro-3-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-3-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-4-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 4-dihydroxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-nitrophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(3-hydroxy-2-pyridyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-1 -naphthyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
WO 94/22807
50
PCT/EP94/01008
N-(3-(trifluoromethyl)phenyl)-N'-(2-hydroxy-5-methoxyphenyl) urea,
N-(3-(trifluoromethyl)phenyl)-N'-(2, 5-dihydroxyphenyl) urea,
N-(3-benzoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carbamoylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-carboxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-hydroxyphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methoxycarbonylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea,
N-(3-methylphenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, or
N-(3-nitrophenyl)-N'-(2-hydroxy-5-chlorophenyl) urea, is prepared.
INTERNATIONAL SEARCH REPORT
Inte- onal Application No
PCT/EP 94/01008
A. CLASSIFICATION OF SUBJECT MATTER
IPC 5 C07C233/29 C07C235/38
C07D213/75 A61K31/165
C07C275/34 C07D213/36 C07D213/63
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols')
IPC 5 C07C C07D A61K
Documentation searched other than minimum documentation to the extent mat such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
C, DOCUMENTS CONSIDERED TO BE RELEVANT
Category '
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
JOURNAL OF PHARMACEUTICAL SCIENCES
vol. 73, no. 12 , December 1984
pages 1871 - 1873
OMAR, A.-M. M.E. ET AL. 'Synthesis and
Evaluation of Novel N-Substituted N'-(3-Hy
droxy-17-oxoestra-l,3,5(10)-trien-2- and
-4-yl) thiourea Derivatives for Binding to
the Estrogen Receptor and Cytotoxic
Activity on MCF-7 Cells'
Compounds VI and IX
see page 1872; figure 1
-/--
1,3,11
Further documents are listed in the continuation of box C.
m
Patent family members are listed in annex.
" Special categories of dted documents :
"A" document defining the general state of the art which is not
considered to be of particular relevance
E" earlier document but published on or after the international
filing date
*L" document which may throw doubts on priority daim(5) or
which is dted to establish the publication date of another
citation or other spedal reason (as specified)
document referring to an oral disclosure, use, exhibition or
other means
document published prior to the international filing date but
later than the priority date claimed
T later document published after the international filing date
or priority date and not in conflict with the application but
dted to understand the prindple or theory underlying the
invention
"X" document of particular relevance; the daimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone
"Y" document of particular relevance; the daimed invention
cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.
'&.' document member of the same patent family
2 August 1994
Date of mailing of the international search report
1 8. G3. 34
Name and mailing address of the ISA
European Patent Office, P.B. 581 8 Patentlaan 2
NL - 2280 HV Rijswijk
Td. ( + 31-70) 340-2040, Tx. 31 651 epo nl,
Fax: ( + 31-70) 340-3016
Authorized officer
Janus, S
page 1 of 2
INTERNATIONAL SEARCH REPORT
Inte' onal Application No
PCT/EP 94/01008
C.(ContmuaOon) DOCUMENTS CONSIDERED TO BE RELEVANT
Category '
Qtation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
A
A
CHEM. PHARM. BULL,
vol. 21, no. 4 , 1973
pages 721 - 728
YAMANA, T. ET AL. 'Stabilization of Drugs.
I. The quantitative Prediction of the
pH-Dependency of Amide and Am" Tide
Hydrolyses by Neighboring Hydroxyl Groups'
Compound 8 (p. 724)
DE,A,22 60 203 (EASTMAN KODAK CO.) 20 June
1973
Compounds II, VI; example 2
US, A, 3 935 262 (LESTINA, G.J. ET AL.) 27
January 1976
Compounds III, X
EP,A,0 354 553 (E.R. SqUIBB & SONS, INC.)
14 February 1990
see the whole document
EP.A.O 477 819 (NEUROSEARCH A/S) 1 April
1992
see the whole document
US, A, 3 331 874 (STECKER, A.C.) 18 July
1967
DE.A.19 12 553 (CIBA, AG) 9 October 1969
1,11
1,11
1,11
1-12
1-12
1
1,3
2
Form PCT/ISA/210 (continuation of second iheet) (July 1993)
page 2 of
2
INTERNATIONAL SEARCH REPORT
International application No.
PCT/EP 94/ 01008
Box 1 Observations where certain claim were found unsearchable (Continuation of hem t of first sheet)
This international search report has not been established to respect of certain claims under Article 17(2X») for the following i
1. _X_ Claims Nos.: 4-7
because they relate to subject matter not required to be searched by this Authority, namely:
Claims 4-7 are directed to a method of treatment of the
animal /human body. The search, which has nevertheless been
carried out, was based on the a 11 edged effects of the
compounds.
2. |_XJ Claims Nos.:
l ° P "if ?{ inl * m *f ional *PPl*ation that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:
Claims searched completely : 2,7, 10, 12
Claims searched Incompletely: 1,3-6,8,9, 11
See annex sheet.
3. | 1 Claims Nos.:
because they are dependent claims and are not drifted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
reL^sX?e U dsfmf dit ' 0nal * eKcil fte * were time,¥ P 10 ^ °y * e applicant, this international search report covers all
2 - [Z3 o* ^^dW^ ^ ms could 08 wwches without effort justifying an additional fee. this Authority did not invite payment
i. Q As only some of the required additional search fees were timely paid by the applicant, this international search report
covers only those claims for which fees were paid, specifically claims Nos.:
*• EH Norequjred additional search fees were timely paid by the applicant. Consequently, this international search report is
restricted to the invention first mentioned in the clairnr, it Iseovered by claims Nos.: ^ tt
Remark on Protest j— "J ^ ^^,1 lelrch feef weTe accompanied by the applicant's
protest.
Q No protest accompanied the payment of additional search fees.
Form PCT/ISA/210 (continuation of first sheet (1)) (July 1992)
International Application No. PCT/EP94/ 01008
FURTHER INFORMATION CONTINUED FROM PCT/ISA/210
Given the very high number of alternatives covered by
the general formula of claim 1, a meaningful search was
not possible 1n a reasonable amount of time. Therefore,
and on the basis of the examples, the search was limited
to compounds of the general formula wherein D and E can-
not be N, and wherein only one of Rll and R12 1s not H.
INTERNATIONAL SEARCH REPORT
information on patent family members
Inte tonal Application No
PCT/EP 94/01008
Patent document
cited in search report
Publication
date
Patent family
member(s)
Publication
date
DE-A-2260203
20-
-06-73
BE-A-
792599
12-06-73
CA-A-
996119
31-08-76
FR-A.B
2162660
20-07-73
GB-A-
1417586
10-12-75
JP-A-
M M^ jk mm M* M M m\
48066441
12-09-73
US-A-
3935262
27-01-76
US-A-
3935263
27-01-76
US-A-3935262
27-
-01-76
BE-A-
792599
12-06-73
CA-A-
996119
31-08-76
DE-A-
2260203
20-06-73
FR-A.B
2162660
20-07-73
GB-A-
1417586
10-12-75
JP-A-
M Mm% A Mm Mt Mi A\ mm
48066441
12-09-73
US-A-
3935263
27-01-76
EP-A-0354553
14-
■02-90
AU-B-
620424
20-02-92
AU-A-
3895989
15-02-90
AU-B-
640844
02-09-93
AU-A-
9007591
13-02-92
JP-A-
2091057
30-03-90
US-A-
5011837
30-04-91
US-A-
5278169
XJL VI 7t
EP-A-0477819
01-
■04-92
AU-B-
635440
18-03-93
AU-A-
8276791
26-03-92
Cm\J WW mV Cm
CA-A-
2052041
25-03-92
JP-A-
4305568
28-10-92
PT-A-
99032
30-11-93
US-A-
5200422
06-04-93
Uo A~ooolo/ 4
FR-A-
1372475
NL-A-
292958
DE-A-1912553
09-
•10-69
BE-A-
730185
22-09-69
FR-A-
2004393
21-11-69
GB-A-
1233125
26-05-71
NL-A-
6904320
23-09-69
SE-B-
370866
04-11-74
US-A-
3689550
05-09-72
Form PCT/IS A/210 (patent family annex) (July 1993)
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